Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to a novel pyridine derivative having an excellent anti- Helicobacterpylori action, a method for producing the compound, and a pharmaceutical composition comprising the compound.
• Gastritis, gastric ulcer and duodenal ulcer are diseases caused by a complicated combination of factors such as stress, genetic predisposition and lifestyle habits.
• Helicobacter pylori H. pylori
• Warren and Marshall succeeded in the isolation and culture of a helical-shaped bacterium from stoma chbiopsy samples in 1983, intensive research has been carried out on the relationship between gastritis, gastric ulcer, duodenal ulcer and gastric cancer, and the subj ect bacterium. As a result, the infection rate of H.
• H. pylori was such that the positive rate is about 4% in normal stomachs, whereas the positive rate is as high as about 83% in chronic gastritis, about 69% in gastric ulcer, about 92% in duodenal ulcer, and about 51% in non-ulcer dyspepsia syndrome ( Martin J. Blaser,: Clin. Infectious Disease, 15; 386-393, 1992 ). Furthermore, H. pylori infection is strongly relevant to the incidence rate of gastric cancer, and thus the International Agency for Research on Cancer affiliated with the World Health Organization (WHO) decided in 1994 that H. pylori is a strongly causative oncogenic factor.
• WHO World Health Organization
• Patent Documents 1 to 4 and 9 propose such medicaments.
• some compounds of the guanidinomethylcyclo hexanecarboxylic acid ester derivatives described in Patent Document 5 exhibit anti- H. pylori activities as represented by an MIC of less than 1 ⁇ g/ml.
• these compounds have a property of very rapidly being decomposed by degrading enzymes in the small intestine or in blood. This property is associated with the compounds which have been designed to have selectivity to H.
• Patent Document 7 there are known pyridine derivatives which are useful as anti-ulcerative agents (see Patent Document 7), pyridine derivatives exhibiting an antibacterial action against Helicobacter pylori (see Patent Document 2), and pyridine derivatives used in suppressing the secretion of gastric acid (see Patent Document 8).
• Patent Document 2 JP-A No. 3-173817 Patent Document 3: JP-A No. 3-48680 Patent Document 4: JP-A No. 7-69888 Patent Document 5: WO 96/06825 Patent Document 6: WO 97/23207 Patent Document 7: JP-A No. 61-50979 Patent Document 8: JP-A No. 58-39622 Patent Document 9: JP-A No. 5-247035
• the inventors of the present invention succeeded in the search for a compound which has a strong anti- H. pylori activity as represented by an MIC of less than 0.3 ⁇ g/ml, exerts no effect on the resident bacteria of human being, and specifically exhibits an antibacterial action against H. pylori, and also discovered a substance exhibiting effectiveness even against those bacteria which are resistant to antibiotic substances such as roxithromycin and ofloxacin, thus completing the present invention.
• the present invention provides the following inventions of (1) to (12).
• R represents a straight-chained or branched hydroxyalkyl group having 5 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof.
• R represents a straight-chained or branched hydroxyalkyl group having 5 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound represented by formula (II):
• R has the same meaning as defined above; and X represents a halogen atom or a sulfonyloxy group.
• a pharmaceutical composition comprising the novel pyridine derivative according to (1) or a pharmaceutically acceptable salt thereof.
• An anti- Helicobacterpylori agent comprising the novel pyridine derivative according to (1) or a pharmaceutically acceptable salt thereof.
• the anti- Helicobacter pylori agent according to (4), wherein the Helicobacter pylori to be treated is a bacterium resistant to macrolide-based antibiotic substances or new quinolone-based antibiotic substances.
• the anti- Helicobacter pylori agent according to (4) further comprising one or two or more drugs suppressing the secretion of gastric acid.
• a prophylactic or therapeutic agent for a disease associated with Helicobacter pylori comprising the novel pyridine derivative according to (1) or a pharmaceutically acceptable salt, as an active ingredient.
• a method for preventing or treating a disease in a mammal comprising administering the novel pyridine derivative according to (1) or a pharmaceutically acceptable salt to the mammal.
• a method for eradicating or controlling Helicobacter pylori in a mammal comprising administering to the mammal in need thereof, the novel pyridine derivative according to (1) or a pharmaceutically acceptable salt thereof in an amount effective for eradicating or controlling Helicobacter pylori.
• a method for preventing or treating a disease associated with Helicobacter pylori in a mammal comprising administering to the mammal in need thereof, the novel pyridine derivative according to (1) or a pharmaceutically acceptable salt thereof in an amount effective for preventing or treating the disease associated with Helicobacter pylori.
• a product comprising the novel pyridine derivative according to (1) or a pharmaceutically acceptable salt thereof, and an instruction or packaging container describing that the compound is used for eradicating or controlling Helicobacter pylori .
• a product comprising the novel pyridine derivative according to (1) or a pharmaceutically acceptable salt thereof, and an instruction or packaging container describing that the compound is used for preventing or treating a disease associated with Helicobacter pylori.
• novel pyridine derivative of the present invention and pharmaceutically acceptable salts thereof exhibit an excellent antibacterial action against Helicobacter pylori ( H. pylori ).
• the novel pyridine derivative of the present invention and pharmaceutically acceptable salts thereof have a very excellent advantage as a medicine that the compounds exert no effect on resident bacteria of human being but specifically exhibit an antibacterial action against H. pylori, and also have an advantage that the compounds exhibit an excellent antibacterial action against H. pylori which is resistant to macrolide-based antibiotic substances or new quinolone-based antibacterial agents.
• use of the novel pyridine derivative of the present invention and pharmaceutically acceptable salts thereof allows eradication of H. pylori in a mammal (particularly, human being).
• R in the formula (I) or (III) represents a straight-chained or branched hydroxyalkyl group having 5 to 10 carbon atoms.
• the "straight-chained or branched hydroxyalkyl group having 5 to 10 carbon atoms" according to the present invention is a group in which at least one hydrogen group of a straight-chained or branched alkyl group having 5 to 10 carbon atoms is substituted by a hydroxyl group.
• the number of hydroxyl groups on the hydroxyalkyl group is not particularly limited, but is preferably 1 to 3, and more preferably 1 to 2, and most preferably one.
• the position of the hydroxyl group in the hydroxyalkyl group is not particularly limited, and the hydroxyl group maybe present at any position on the carbon chain. However, it is preferable that one hydroxyl group (if a plurality of hydroxyl groups are present, at least one among those) is present on a carbon atom at one end of the carbon chain. That is, at least one hydroxyl group on the hydroxyalkyl group is preferably a group formed by substituting a hydrogen group on -CH 3 at one end of a straight-chained or branched alkyl group having 5 to 10 carbon atoms.
• the carbon number of the R group would be suitably any number within the range of 5 to 10, but it is particularly preferable that the carbon number is 8.
• the carbon number of the R group is preferably in the range of 5 to 10, more preferably in the range of 6 to 9, and particularly preferably 8, from the viewpoint of the intensity of the anti- Helicobacter pylori activity.
• the R group may be any of a straight chain and a branched chain, but it is particularly preferable that the group is straight-chained.
• Particularly preferred examples of the R group include -(CH 2 ) 5 OH, -(CH 2 ) 6 OH, -(CH 2 ) 7 OH, -(CH 2 ) 8 OH, -(CH 2 ) 9 OH, and -(CH 2 ) 10 OH.
• X represents a halogen atom or a sulfonyloxy group.
• the halogen atom means any of fluorine, chlorine, bromine and iodine.
• the sulfonyloxy group various sulfonyloxygroupscanbeused, and typically an alkyl sulfonyloxy group which may be substituted, or an arylsulfonyloxy group which may be substituted can be used.
• the alkylsulfonyloxy group may be exemplified by a lower alkylsulfonyloxy group such as a methanesulfonyloxy group or an ethanesulfonyloxy group.
• the alkyl contained in the alkylsulfonyloxy group may be further substituted with a substituent such as halogen.
• the arylsulfonyloxy group may be exemplified by a benzenesulfonyloxy group or the like.
• the aryl contained in the arylsulfonyloxy group may be further substituted with a substituent.
• the pyridine derivative (I), which is the target compound of the present invention, can be produced by allowing raw material compounds (II) and (III) to react. It is favorable that the subj ect reaction is performed in the presence of a base.
• the base include alkali metal hydrides such as sodium hydride and potassium hydride; alcoholates such as potassium t-butoxide, sodium propoxide, sodium ethoxide and sodium methoxide; alkali metal carbonates such as potassium carbonate and sodium carbonate; organic amines such as triethylamine; and the like.
• the solvent to be used in the reaction for example, alcohols such as methanol and ethanol, dimethylsulfoxide and the like may be mentioned.
• the amount of the base used in the reaction is usually a slightly excess amount with respect to one equivalent, but a large excess of base may also be used. That is, the amount is 1 to 10 equivalents, and preferably 1 to 4 equivalents.
• the reaction temperature is typically from -40°C to a temperature near the boiling point of the solvent used, and preferably 0°C to 60°C.
• the reaction time is about 0.2 to 24 hours, and preferably 0.5 to 2 hours.
• the target compound (I) produced by the reaction can be isolated and purified by conventionally used means such as recrystallization and chromatography.
• the compound (I) of the present invention may be converted to a pharmacologically acceptable salt by conventionally used means.
• a pharmacologically acceptable salt examples include hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate and the like.
• the compound according to the present invention or a salt thereof may be in the form of hydrate, or a solvate with a lower alcohol or the like.
• the scope of the compound according to the present invention or a salt thereof includes those hydrate or solvate forms as well.
• a chloro derivative (VI) can be obtained by reacting a nitro compound represented by formula (IV) with concentrated hydrochloric acid. When the chloro derivative (VI) is reacted with an alcohol derivative ROH (IV) in the presence of a base, an alkoxy derivative of formula (VII) can be obtained.
• the base includes, for example, alkali metals such as lithium, sodium and potassium; alkali metal hydrides such as sodium hydride and potassium hydride; alcoholates such as potassium t-butoxide, sodium propoxide, sodium ethoxide and sodium methoxide; carbonates or hydrogen carbonates of alkali metals such as potassium carbonate, lithium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate; alkali metals such as potassium, sodium and lithium; alkaline hydroxides such as sodium hydroxide and potassium hydroxide; and the like.
• alkali metals such as lithium, sodium and potassium
• alkali metal hydrides such as sodium hydride and potassium hydride
• alcoholates such as potassium t-butoxide, sodium propoxide, sodium ethoxide and sodium methoxide
• carbonates or hydrogen carbonates of alkali metals such as potassium carbonate, lithium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate
• alkali metals such as potassium, sodium
• ethers such as tetrahydrofuran, dioxane and t-butyl methyl ether; ketones such as acetone and methyl ethyl ketone; and aromatic hydrocarbons such as benzene, toluene, xylene and trimethylbenzene
• examples of other usable solvents include acetonitrile, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like.
• reaction temperature a suitable temperature is selected from -70°C to a temperature near the boiling point of the solvent.
• the reaction time is about 1 to 48 hours.
• a 2-hydroxymethylpyridine derivative represented by formula (IX) can be produced by subjecting the compound (VIII) to alkaline hydrolysis.
• alkali include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and the like.
• solvent to be used for example, methanol, ethanol, water and the like may be mentioned.
• the reaction time is about 0.1 to 2 hours.
• a 2-halogenomethylpyridine derivative represented by formula (III) can be produced by halogenating the compound (IX) with a chlorinating agent such as thionyl chloride, a brominating agent or an iodinating agent.
• a 2-sulfonyloxymethylpyridine derivative represented by formula (III) can be produced by performing sulfonyloxylation with various sulfonyloxylating agents, for example, an alkylsulfonyloxylating agent such as methanesulfonyl chloride or ethanesulfonyl chloride, or an aromatic sulfonyloxylating agent such as benzenesulfonyl chloride.
• the solvent to be used for example, chloroform, dichloromethane, tetrachloroethane, benzene, toluene, tetrahydrofuran, dioxane, methyl t-butyl ether, dioxane, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like may be mentioned.
• the reaction temperature a suitable temperature is selected typically from -70°C to a temperature near the boiling point of the solvent.
• the reaction time is about 0.1 to 2 hours.
• the compound of the present invention or a salt thereof can eradicate or control Helicobacter pylori in the body of an animal belonging to mammal (typically, human being). That is, the compound of the present invention or a salt thereof is effective as an anti- Helicobacter pylori agent.
• the present invention also provides a method for eradicating or controlling Helicobacter pylori in a mammal, the method comprising administering an effective amount of the compound of the present invention or a salt thereof to a mammal in need of the method.
• the present invention also provides a use of the compound of the present invention or a salt thereof, for the manufacture of an anti- Helicobacter pylori agent.
• a medicament containing the compound of the present invention or a salt thereof is effective for preventing or treating a disease associated with Helicobacter pylori.
• the "disease associated with Helicobacter pylori " according to the present invention refers to a disease which is caused or exacerbated by the infection, survival or propagation of Helicobacter pylori in the living body.
• the "disease associated with Helicobacter pylori " is a disease in which the symptoms may be improved by removing Helicobacter pylori .
• Examples of such disease include gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia syndrome, gastric MALT lymphoma, hyperplastic polyp of the stomach, gastric cancer (particularly, gastric cancer developing after endoscopic excision of early gastric cancer) and the like.
• Other examples of the "disease associated with Helicobacter pylori " include digestive system cancer and pancreatitis caused by Helicobacter pylori.
• the compound of the present invention or a salt thereof can delay or impede the progress of digestive system cancer caused by Helicobacter pylori.
• As another example of the "disease associated with Helicobacter pylori ,” inflammatory bowel disease caused by Helicobacter pylori may be mentioned.
• various dosage forms can be employed according to the purpose of prevention or treatment, and examples of the administrable formation include powders, fine granules, granules, tablets, capsules, dry syrups, syrups, injections and the like.
• a pharmaceutical composition containing the compound of the present invention can include a pharmaceutically acceptable carrier or excipient, or other additives.
• an excipient In the case of preparing an oral solid preparation, an excipient, and if necessary, a binding agent, a disintegrant, a gliding agent, a colorant, a savoring or flavoring agent and the like can be added to the compound of the present invention, and then tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods.
• a binding agent e.g., a binding agent, e.g., a binding agent, a disintegrant, a gliding agent, a colorant, a savoring or flavoring agent and the like
• a binding agent e.g., a binding agent, a disintegrant, a gliding agent, a colorant, a savoring or flavoring agent and the like
• a binding agent e.g., a disintegrant, a gliding agent, a colorant, a savoring or flavoring
• binding agent water, ethanol, gum arabic, tragacanth, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, gelatin, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone and the like can be used.
• disintegrant powdered gelatin, crystalline cellulose, dry starch, sodium alginate, pectin, powdered agar, carboxymethylcellulose, sodium hydrogen carbonate, calcium carbonate, calcium citrate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and the like can be used.
• gliding agent silica, purified talc, stearic acid salts, borax, polyethylene glycol and the like can be used.
• colorant those having been approved for addition, such as titanium oxide and iron oxide, can be used.
• sucrose, orange peel, citric acid, tartaric acid and the like can be used.
• a savoring agent in the case of preparing an oral liquid preparation, a savoring agent, a buffering agent, a stabilizer, a flavoring agent and the like can be added to the compound of the present invention, and then liquid preparations for internal use, syrups, elixirs and the like can be produced by conventional methods.
• the savoring or flavoring agent those mentioned above may be used.
• the buffering agent sodium citrate and the like may be mentioned.
• the stabilizer tragacanth, gum arabic, gelatin and the like may be mentioned.
• a pH adjusting agent, a buffering agent, a stabilizer, an isotonic agent, a local anesthetic and the like can be added to the compound of the present invention, and then injectable preparations for subcutaneous, intramuscular and intravenous uses can be produced by conventional methods.
• the pH adjusting agent and buffering agent in this case, sodium citrate, sodium acetate, sodium phosphate and the like may be mentioned.
• the stabilizer sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like may be mentioned.
• procaine hydrochloride, lidocaine hydrochloride and the like may be mentioned.
• isotonic agent sodium chloride, glucose and the like may be mentioned as examples.
• the pharmaceutical composition and prophylactic or therapeutic agent of the present invention described in the claims can further contain one or two ormore dextrins, in addition to the novel pyridine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
• dextrins examples include ⁇ -dextrin, ⁇ -dextrin, ⁇ -dextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin and the like, but are not limited to these.
• the pharmaceutical composition and prophylactic or therapeutic agent of the present invention described in the claims can further contain one or two or more drugs suppressing the secretion of gastric acid, in addition to the novel pyridine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
• drugs suppressing the secretion of gastric acid include H2 blockers, proton pump inhibitors and the like may be mentioned.
• H2 blocker that can be used in the present invention include famotidine, ranitidine and the like
• examples of the proton pump inhibitor that can be used in the present invention include lansoprazole, omeprazole, rabeprazole, pantoprazole and the like, but the examples are not to be limited to these.
• the amount of the compound of the present invention to be incorporated in each of the unit dosage forms may vary depending on the symptoms of the patient in need of application of the compound, or on the formulation, but in general, it is desirable to set the amount in each unit dosage form to about 1 to 1200 mg for oral preparations, and about 0.1 to 500 mg for injectable preparations.
• the amount of daily administration of a medicament being in the above-described dosage form varies with the symptoms, body weight, age, gender and the like of the patient, and thus cannot be determined as a fixed value; however, the amount may be usually about 0.1 to 5000 mg, and preferably 1 to 1200 mg, per day for an adult, and it is preferable that this amount is administered once or in about 2 to 4 divided portions in one day.
• reaction liquor was cooled, and then concentrated under reduced pressure and dried to solid, to obtain 53.3 g of concentrated residue, and the concentrated residue was purified using a silica gel column to obtain 25.0 g of 4- (5-hydroxypentyloxy) -2, 3-dimethylp yridine-N-oxide.
• reaction liquor was adjusted to pH 9 using a saturated aqueous solution of sodium carbonate, and then the resultant was extracted with 90 mL of chloroform, dried over magnesium sulfate, then concentrated and dried to solid, to obtain 7.8 g of 4-(5-hydroxypentyloxy)-2-chloromethyl-3-methyl pyridine.
• a solution prepared by adding 7.5 g (0.029 mol, 1.0 eq.) of 4-(5-hydroxypentyloxy)-2-chloromethyl-3-methylp yridine and 3.5g (0.023mol, 0.8 eq.) of 2-mercaptobenzimidazole with cooling in ice water and stirring, a solution of 1. 4 g (0.
• reaction liquor was adjusted to pH 8 using a saturated aqueous solution of sodium carbonate, and then the dichloromethane layer was dried over magnesium sulfate, then concentrated and dried to solid, to obtain 6.7 g of 4-(6-hydroxyhexyloxy)-2-chloromethyl-3-methyl pyridine as an orange-colored oily matter (yield 89.3%).
• reaction liquor was adjusted to pH 8 using 300 g of a saturated aqueous solution of sodium carbonate, and then the dichloromethane layer was dried over magnesium sulfate, then concentrated and dried to solid, to obtain 25.2 g of 4-(8-hydroxyoctyloxy)-2-chloromethyl-3-methylpyridine as an orange-brown oily matter (yield 98.1%).
• the concentrated residue was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 200 mL of water. The organic layer was left to stand overnight, and then crystals were precipitated. Thus, 20 mL of methanol was added, and the mixture was heated to 42°C to dissolve. Then, 27.6 g of silica gel was added, the mixture was stirred for 30 minutes, and then the silica gel was removed by filtration. The filtrate was concentrated under reduced pressure, to obtain 9.0 g of orange-white crystals. The crystals were suspended in 135 g (15 vol) of ethyl acetate, the suspension was heated to 57°C, and then 12.8 g of methanol was added to completely dissolve the crystals.
• Crystals were precipitated by standing the solution to cool. After aging at 20°C for 1 hour, the crystals were collected by filtration. The crystals were dried under reduced pressure, to obtain 3.7 g of colorless crystals of 2-[ ⁇ 4-(8-hydroxyoctyloxy)-3-methylpyridin-2-yl ⁇ methylthio]-1H-benzimidazole (HPLC purity: 98.4 Area%, yield 23.1%).
• reaction liquor was adjusted to pH 9 using a saturated aqueous solution of sodium carbonate, and then the extracted dichloromethane layer was dried over magnesium sulfate, then concentrated and dried to solid, to obtain 17.2 g of 4-(9-hydroxynonyloxy)-2-chloromethyl-3-methylpyridine (yield 74.1%).
• the concentrated residue was dissolved in 377 mL of ethyl acetate, and then the organic layer was washed with 302 mL of water. Since the organic layer had crystals precipitated, 30 mL of methanol was added, and the mixture was heated to 35°C to dissolve. Then, 41. 6 g of silica gel was added, the mixture was stirred for 30 minutes, and then silica gel was removed by filtration. The filtrate was concentrated under reduced pressure, to obtain 13.9 g of an orange-colored oily matter. The oily matter was heated in 208.5 g (15 vol) of ethyl acetate to dissolve, and then crystals were precipitated by standing the solution to cool.
• reaction liquor was adjusted to pH 8 using a saturated aqueous solution of sodium carbonate, and then the extracted dichloromethane layer was dried over magnesium sulfate, then concentrated and dried to solid, to obtain 10.6 g of 4-(10-hydroxydecyloxy)-2-chloromethyl-3-me thylpyridine (yield 96.4%).
• the concentrated residue was dissolved in a liquid mixture of 250 mL of ethyl acetate and 2 mL of methanol, and then the organic layer was washed with 200 mL of water. 18.0 g of silica gel was added to the organic layer, the mixture was stirred for 30 minutes, and then the silica gel was removed by filtration. The filtrate was concentrated under reduced pressure, to obtain 13.4 g of yellow-white crystals.
• the crystals were suspended in 201 g (15 vol) of ethyl acetate, the suspension was heated to 55°C, and then 17.5 g of methanol was added to completely dissolve the crystals. Crystals were precipitated by standing the solution to cool.
• the compounds of the present invention (Examples 1 to 6) were acknowledged to have strong antibacterial effects against H. pylori, as equivalently strong as the various antibacterial agents (control drugs 1 to 4).
• the compounds of the present invention showed anti- Helicobacter pylori activities that were clearly 10 times or more stronger than the activities of the existing similar two compounds (comparative compounds 1 and 2).
• the compounds of Comparative Examples are the above-mentioned 2-[ ⁇ 4-(2-hydroxyethoxy)-3-methylpyridin-2-yl ⁇ methylthio]-1H -benzimidazole (comparative compound 1) and 2-[ ⁇ 4-(3-hydroxy propoxy)-3-methylpyridin-2-yl ⁇ methylthio]-1H-benzimidazole (comparative compound 2).
• the various numerical values represent the minimum inhibitory concentration (MIC, ⁇ g/ml) of various test objects against various bacterial species, RXM represents roxithromycin, and OFLX represents ofloxacin.
• the compounds of the present invention showed equivalent or stronger antibacterial activities to roxithromycin or ofloxacin compared to the standard strains and clinical isolates. Furthermore, the compounds also exhibited strong antibacterial activities against the roxithromycin- or ofloxacin-resistant clinical isolates. That is, the compounds were acknowledged to exhibit strong antibacterial activities even for the strains that are resistant to roxithromycin from the macrolide family and ofloxacin from the new quinolone family.
• Table 3 shows the minimum inhibitory concentration (MIC, ⁇ g/ml) against the standard strains NCTC11637 and NCTC11916 of the compounds ((a) to (f)) having structures that are similar to the structure of the compound of the present invention. These are data described in Table 6 of JP-A No. 7-69888 .
• [Table 3] Effects of existing pyridine derivatives on Helicobacter pylori Test object Bacterial species (a) (b) (c) (d) (e) (f) RXM NCTC11637 50 12.5 6.25 1.56 0.8 0.8 0.2 NCTC11916 50 12.5 12.5 1.56 1.56 1.56 0.1
• Example 4 From a comparison of the data of Table 2 and Table 3, it can be seen that the compounds of the present invention (Examples 1 to 6) have activities against the standard strain NCTC11637 that are about 2.7-fold to 1,667-fold, and activities against the strain NCTC11916 that are about 5.2-fold to 1,667-fold, compared to the activities of the compounds of the same class ((a) to (f)).
• Example 4 was found to have the strongest activity among the compounds of the same class, and to have an activity as strong as 26. 6-fold against the standard strain NCTC11637 and 52-fold against the standard strain NCTC11916, compared to the activities of the compounds (e) and (f).
• the various bacteria were cultured at 37°C for 20 to 48 hours by conventional methods, and the minimum inhibitory concentrations (MIC, ⁇ g/ml) were determined.
• MIC minimum inhibitory concentration
• Each of the test objects were dissolved in a 1% DMSO solution.
• GEM gentamycin
• any of the compounds of Examples 1 to 6 was not recognized to have an antibacterial action against various gram-negative bacteria and gram-positive bacteria.
• gentamycin from the aminoglycoside family exhibited a strong antibacterial action against various gram-negative bacteria and gram-positive bacteria. From this, it was suggested that the compounds of the present invention have no influence at all on the intestinal bacteria.
• Tablets each weighing 145.2 mg were prepared at the above mixing proportions according to a conventional method.
• a granular preparation weighing 1000 mg per package was prepared at the above mixing proportions according to a conventional method.
• An injectable preparation was prepared at the above mixing proportions according to a conventional method.
• a syrup preparation was prepared at the above mixing proportions according to a conventional method.
• Tablets each weighing 110 mg were prepared at the above mixing proportions according to a conventional method.
• novel pyridine derivative of the present invention and pharmaceutically acceptable salts thereof are clinically very promising medicines, since the compounds have no effects on the resident bacteria of human being, exhibit specific antibacterial action against H. pylori , and also exhibit strong antibacterial activities against strains that are resistant to antibacterial agents.

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